A compound of the formula (IV):
wherein R1 and R2 each independently represents halogen, alkyl, alkoxy, nitro or cyano, R3 represents hydrogen or an organic residue, R4 represents an organic residue and R5 represents hydrogen or an organic residue, is known to be pharmacologically active, useful as an antiviral agent or an agent for treatment of AIDS (WO 96/10019).
WO 96/10019 has disclosed the compound of the formula (IV) prepared through the condensation of thiophenol or disulfide and 4-halogenoimidazole derivatives. However, this reaction requires the use of a strong base such as lithium hydride, sodium hydride or potassium hydride. Moreover, the reaction must be carried out under heating because it does not proceed at room temperature. This reaction is, therefore, inappropriate for industrial process. We have already filed an application concerning the new synthetic route for stable supply of the compound of the formula (IV) (PCT/JP97/04708). It is necessary to establish a process for producing a compound of the formula (II):
wherein Hal1 represents halogen and R1 and R2 are as defined above, one of the starting materials used in the new synthetic route, which is applicable to a convenient, economical and large-scale production.
On the other hand, some processes for producing a similar compound to that of the formula (II) of the present invention have been known. Usually used process for producing arylsulfenyl halide is a process which comprises allowing a halogenating agent to react with a disulfide derivative prepared by the oxidization of an aromatic thiol derivative. The process for preparing the disulfide derivative from the aromatic thiol derivative has been described in, for example, Chem. Ind., 501 (1964), Synthesis-stuttgart, (5), 378–380 (1989), J. Organomet. Chem., 368 (3), 295–302 (1989) and Tetrahedron Letter, 31 (35), 5007–5010 (1990). The process which comprises allowing the halogenating agent to react with the disulfide derivative has been described in, for example, Org. Synth., II, 455, (1943).
Another known method is the process which comprises allowing the halogenating agent to react with the sulfide derivative substituted with benzyl or the like which is prepared from the aromatic thiol derivative. The process for preparing the sulfide derivatives substituted with benzyl or the like from the aromatic thiol derivatives has been described in, for example J. Org. Chem., 42 (26), 4275 (1977), Tetrahedron Letter, 635, (1969) and Chem. Pharm. Bull., 40 (8), 1986–1989 (1992). The process which comprises allowing the halogenating agent to react with the sulfide derivatives substituted with benzyl or the like has been described in, for example J. Org. Chem., 28, 1903 (1963). These conventional methods, however, require many steps for preparing the starting materials, disulfide derivatives and sulfide derivatives. The residues such as benzyl and the like are generally expensive and inappropriate for the industrial process.
Some processes for producing the aromatic thiol derivatives which are starting materials of the above-mentioned disulfide derivatives and sulfide derivatives have been known. Examples of the processes include the method which comprises allowing sulfur to react with the Grignard reagent prepared from the commercially available corresponding halide (Chem. Ber., 72, 594 (1939)), the method which comprises preparing xantate from the diazo intermediates prepared from the commercially available corresponding aniline derivatives and hydrolyzing at the next step (Org. Synth. Coll., Vol. 3, 809 (1955)), the method of the thermal rearrangement of thiourethane prepared by the acylation of easily available phenol derivatives and further hydrolysis (J. Org. Chem., Vol. 31, 3980 (1966)), and the chlorination of the methylthio derivatives prepared by the substitution reaction of the methylmercaptan with the corresponding halide and further hydrolysis (JP-A 9-40636).
These methods are, however, inappropriate for the industrial process because they not only require many steps but also proceed via unstable intermediates such as the Grignard reagents and the diazo derivatives. Indeed, these methods are difficult to apply to the industrial process because the obtained arylsulfenyl halide is expensive.
Examples of the other synthetic methods concerning arylsulfenyl halide include the process for producing arylsulfenyl halide which comprises allowing the halogenating agent to react with the alkyl aryl sulfide derivatives prepared from the halogenated benzene derivatives.
As the process for producing alkylarylsulfide, the process for producing 2,5-dichlorophenylalkylsulfide from 1,2,4-trichlorobenzene is disclosed in JP-A 9-56760. In Tetrahedron Letters, 1982, 23, 4629, the process for producing 4-chlorophenylalkylsulfide from 1,4-dichlorobenzene is disclosed.
As the process for producing arylsulfenyl halide from alkylarylsulfide, the process for producing 4-isopropoxyphenylsulfenylhalide from 4-isopropoxyphenyl isopropyl sulfide is disclosed (Synthesis, 1976, 451).
These literatures and the like do not disclose the above-described process using 3,5-dihalogenated benzene derivatives as a starting material.
In J. Org. Chem., 1980, 45, 3880–3884, 3,5-dichlorophenylsulfenylchloride is disclosed, but a process thereof is not mentioned at all.